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Novel targets beyond vascular endothelial growth factor-A inhibition: improving vision with neovascular age-related macular degeneration treatment

Eye volume 39, pages 3045–3057 (2025)Cite this article

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Abstract

The primary goal in the management of neovascular age-related macular degeneration (nAMD) is to optimise visual acuity outcomes for patients. Landmark clinical trials have demonstrated improved visual outcomes with standard-of-care vascular endothelial growth factor (VEGF) inhibitors, principally targeting a single ligand (VEGF-A). However, in the real-world setting, not all patients attain optimal visual outcomes with these monotherapies. The role of the VEGF-A and VEGF receptor (VEGFR)-2 axis in angiogenesis and vascular permeability is well characterised, but other VEGF family members, including VEGF-C and VEGF-D, which activate VEGFR-2 and VEGFR-3, have also been implicated in nAMD pathogenesis. This may explain the heterogeneous responses observed with current therapies that primarily inhibit VEGF-A signalling, and in patients who continue to lose vision despite treatment, the consequences can be profound. Vision loss affects daily living and can lead to increased cost of care and susceptibility to falls and injuries. This review will explore the VEGF family of ligands and receptors and their role in nAMD, as well as novel therapeutics in development that target mediators beyond VEGF-A with the potential to provide improved vision benefits to patients. In particular, sozinibercept, an investigational trap biologic inhibitor of VEGF-C and VEGF-D ligands, has shown promising efficacy with superior vision gains when used in combination with ranibizumab dosed monthly (standard-of-care therapy) vs. standard-of-care alone (i.e. monthly ranibizumab). This adds to the increasing evidence that multifaceted approaches that target the VEGF family beyond VEGF-A have the potential to provide better vision outcomes for patients with nAMD.

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Fig. 1: The VEGF family in nAMD pathogenesis and treatment.

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Acknowledgements

Medical writing support was provided by Veronika Khariv, PhD, CMPP, of IMPRINT Science, New York, NY, USA, and was funded by Opthea.

Funding

Medical writing support was provided by IMPRINT Science and was funded by Opthea.

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Authors and Affiliations

  1. Sierra Eye Associates, Reno, NV, USA

    Arshad M. Khanani

  2. University of Nevada, Reno School of Medicine, Reno, NV, USA

    Arshad M. Khanani

  3. Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA

    Sophie J. Bakri

  4. Mid Atlantic Retina, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA

    Carl Regillo

  5. Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA

    Christina Y. Weng

  6. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    Tien Y. Wong

  7. Beijing Visual Science and Translational Eye Research Institute, School of Clinical Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua Medicine, Tsinghua University, Beijing, China

    Tien Y. Wong

  8. Opthea Limited, Opthea Limited, South Yarra, VIC, Australia

    Megan E. Baldwin, John J. Han & Ian M. Leitch

Authors
  1. Arshad M. Khanani
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  2. Sophie J. Bakri
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  3. Carl Regillo
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  4. Christina Y. Weng
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  5. Tien Y. Wong
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  6. Megan E. Baldwin
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  7. John J. Han
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  8. Ian M. Leitch
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Contributions

Conceptualisation: AK IL; Original draft: IL, JH; Writing (review and editing): AK, SB, CR, CW, TW, MB, JH, IL; Funding acquisition: AK.

Corresponding author

Correspondence to Arshad M. Khanani.

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Competing interests

A.K. consults for AbbVie; ADARx Pharmaceuticals; Adverum; Alcon; Alkeus; Allgenesis; Amgen; Annexin; Annexon; Apellis Pharmaceuticals; Ashvattha Therapeutics; Astellas; Aviceda Therapeutics; Beacon Therapeutics; Boehringer Ingelheim; Clearside Biomedical; Complement Therapeutics; 4DMT; Exegenesis; EyePoint Pharmaceuticals; Fronterra Therapeutics; Genentech; Gyroscope Therapeutics; Harrow; i-Lumen Scientific; InFocus; Iveric Bio, An Astellas Company; Janssen Pharmaceuticals; Kodiak Sciences; Kriya Therapeutics; Kyowa Kirin; Merit; Neurotech; Nanoscope; Novartis; Ocular Therapeutix; Oculis; Ocuphire; OcuTerra; Ollin; Olive BioPharma; Opthea; Opus Genetics; Oxular; Oxurion; Perfuse; Ray Therapeutics; Recens Medical; Regeneron Pharmaceuticals; Regenxbio; Revive; RevOpsis; Roche; Samsung; Sanofi; Stealth BioTherapeutics; Surrozen; Thea Pharma; Therini; Unity Biotechnology; Vanotech; Vial; and ZipBio. He receives research support from Aviceda Therapeutics; Adverum; Alexion; Annexon; Apellis Pharmaceuticals; Astellas; Aviceda Therapeutics; Complement Therapeutics; 4DMT; EyePoint Pharmaceuticals; Exegenesis; Genentech; Gyroscope Therapeutics; Iveric Bio, An Astellas Company; Janssen; Kodiak; Kyowa Kirin; Neurotech; Ocular Therapeutix; Oxular; Regenxbio; Roche; Sanofi; and Vanotech. He has held stock options in Ashvattha Therapeutics; Aviceda Therapeutics; Oculis; Opthea; PolyPhotonix; Recens Medical; Perfuse; RevOpsis; Vial; and ZipBio. He is on the board of directors for Oculis. S.B. consults for AbbVie; Adverum; Allergan; Amgen; Annexon; Apellis; Aviceda; Cholgene; EyePoint; Genentech; i-Lumen; Iveric Bio, An Astellas Company; Kala; Neurotech; Novartis; Ocular Therapeutix; Opthea; Outlook; Pixium; Regeneron; Regenxbio; Rejuvitas; Revana; Roche; VoxelCloud; and Zeiss. She receives research funding from Lowy Medical Foundation and Regenxbio. C.R. consults for 4DMT; Adverum; Alcon; Allergan; Annexon; Apellis; Astellas; Aviceda; Boehringer Ingelheim; Chengdu Kanghong; Clearside; Cognition Therapeutics; Endogena; EyePoint; Genentech, Inc.; Iveric Bio, An Astellas Company; Janssen; jCyte; Kodiak Sciences; Kyoto Drug Development; Lineage Cell Therapeutics; Merck; NGM Bio; Novartis; Ocugen; Ocuphire; OcuTerra; Opthea; Oxular; Ray; Regeneron; Regenxbio; Sanofi; Stealth; Théa; Zeiss; and ZipBio; He receives research support from 4DMT; Adverum; Allergan; Annexon; Apellis; Astellas; EyePoint; Genentech, Inc.; Gyroscope; Iveric Bio, An Astellas Company; Kodiak Sciences; Lineage Cell Therapeutics; NGM Bio; Novartis; Ocugen; Opthea; Regeneron; and Regenxbio. He has stock options in Aviceda and Ocugen. C.W. consults for Alcon; Alimera; Allergan/AbbVie; Apellis; DORC; EyePoint; Genentech; Iveric Bio, An Astellas Company; Opthea; Regeneron; Regenxbio; and Zeiss. She received research support from AGTC, Alimera Sciences, and DRCR Retina Network. She received royalties from Springer Publishing. She holds voluntary leadership positions with the American Society of Cataract and Refractive Surgery, American Society of Retina Specialists, Retina Society, and Women in Ophthalmology. T.W. consults for Aldropika Therapeutics; Astellas; Bayer; Boehringer Ingelheim; Eden Ophthalmic; Genentech; Iveric Bio, An Astellas Company; Novartis; Oxurion; Plano; Roche; Sanofi; Shanghai Henlius; and Zhaoke Pharmaceutical; and holds patents for and is the cofounder of EyRiS and Visre. M.B., J.H., and I.L. are employees and stockholders of Opthea Limited.

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Khanani, A.M., Bakri, S.J., Regillo, C. et al. Novel targets beyond vascular endothelial growth factor-A inhibition: improving vision with neovascular age-related macular degeneration treatment. Eye 39, 3045–3057 (2025). https://doi.org/10.1038/s41433-025-04042-3

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